rs11780911

chr8-143930378-G-Achr8-143930378-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201384.3(PLEC):c.2457+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.776 in 1,570,352 control chromosomes in the GnomAD database, including 482,209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (36050 hom., cov: 35)
  • Exomes 𝑓: 0.79 (446159 hom.)
• Consequence: PLEC NM_201384.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00001679
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -2.51

Genes affected

PLEC (HGNC:9069): (plectin) Plectin is a prominent member of an important family of structurally and in part functionally related proteins, termed plakins or cytolinkers, that are capable of interlinking different elements of the cytoskeleton. Plakins, with their multi-domain structure and enormous size, not only play crucial roles in maintaining cell and tissue integrity and orchestrating dynamic changes in cytoarchitecture and cell shape, but also serve as scaffolding platforms for the assembly, positioning, and regulation of signaling complexes (reviewed in PMID: 9701547, 11854008, and 17499243). Plectin is expressed as several protein isoforms in a wide range of cell types and tissues from a single gene located on chromosome 8 in humans (PMID: 8633055, 8698233). Until 2010, this locus was named plectin 1 (symbol PLEC1 in human; Plec1 in mouse and rat) and the gene product had been referred to as "hemidesmosomal protein 1" or "plectin 1, intermediate filament binding 500kDa". These names were superseded by plectin. The plectin gene locus in mouse on chromosome 15 has been analyzed in detail (PMID: 10556294, 14559777), revealing a genomic exon-intron organization with well over 40 exons spanning over 62 kb and an unusual 5' transcript complexity of plectin isoforms. Eleven exons (1-1j) have been identified that alternatively splice directly into a common exon 2 which is the first exon to encode plectin's highly conserved actin binding domain (ABD). Three additional exons (-1, 0a, and 0) splice into an alternative first coding exon (1c), and two additional exons (2alpha and 3alpha) are optionally spliced within the exons encoding the acting binding domain (exons 2-8). Analysis of the human locus has identified eight of the eleven alternative 5' exons found in mouse and rat (PMID: 14672974); exons 1i, 1j and 1h have not been confirmed in human. Furthermore, isoforms lacking the central rod domain encoded by exon 31 have been detected in mouse (PMID:10556294), rat (PMID: 9177781), and human (PMID: 11441066, 10780662, 20052759). The short alternative amino-terminal sequences encoded by the different first exons direct the targeting of the various isoforms to distinct subcellular locations (PMID: 14559777). As the expression of specific plectin isoforms was found to be dependent on cell type (tissue) and stage of development (PMID: 10556294, 12542521, 17389230) it appears that each cell type (tissue) contains a unique set (proportion and composition) of plectin isoforms, as if custom-made for specific requirements of the particular cells. Concordantly, individual isoforms were found to carry out distinct and specific functions (PMID: 14559777, 12542521, 18541706). In 1996, a number of groups reported that patients suffering from epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) lacked plectin expression in skin and muscle tissues due to defects in the plectin gene (PMID: 8698233, 8941634, 8636409, 8894687, 8696340). Two other subtypes of plectin-related EBS have been described: EBS-pyloric atresia (PA) and EBS-Ogna. For reviews of plectin-related diseases see PMID: 15810881, 19945614. Mutations in the plectin gene related to human diseases should be named based on the position in NM_000445 (variant 1, isoform 1c), unless the mutation is located within one of the other alternative first exons, in which case the position in the respective Reference Sequence should be used. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-143930378-G-A is Benign according to our data. Variant chr8-143930378-G-A is described in ClinVar as [Benign]. Clinvar id is 129938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143930378-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.81 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201378.4	c.2415+6C>T		splice_donor_region_variant, intron_variant		ENST00000356346.7
PLEC	NM_201384.3	c.2457+6C>T		splice_donor_region_variant, intron_variant		ENST00000345136.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8	c.2457+6C>T		splice_donor_region_variant, intron_variant		1	NM_201384.3
PLEC	ENST00000356346.7	c.2415+6C>T		splice_donor_region_variant, intron_variant		1	NM_201378.4

Frequencies

GnomAD3 genomes AF: 0.664 AC: 100959 AN: 152020 Hom.: 36053 Cov.: 35

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.818

Gnomad AMR AF: 0.645

Gnomad ASJ AF: 0.800

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.760

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.816

Gnomad OTH AF: 0.696

GnomAD3 exomes AF: 0.714 AC: 129447 AN: 181266 Hom.: 47573 AF XY: 0.718 AC XY: 71602 AN XY: 99688

Gnomad AFR exome AF: 0.381

Gnomad AMR exome AF: 0.623

Gnomad ASJ exome AF: 0.796

Gnomad EAS exome AF: 0.620

Gnomad SAS exome AF: 0.607

Gnomad FIN exome AF: 0.766

Gnomad NFE exome AF: 0.822

Gnomad OTH exome AF: 0.749

GnomAD4 exome AF: 0.788 AC: 1116879 AN: 1418214 Hom.: 446159 Cov.: 69 AF XY: 0.783 AC XY: 550700 AN XY: 703010

Gnomad4 AFR exome AF: 0.372

Gnomad4 AMR exome AF: 0.626

Gnomad4 ASJ exome AF: 0.796

Gnomad4 EAS exome AF: 0.637

Gnomad4 SAS exome AF: 0.612

Gnomad4 FIN exome AF: 0.760

Gnomad4 NFE exome AF: 0.827

Gnomad4 OTH exome AF: 0.758

GnomAD4 genome AF: 0.664 AC: 100982 AN: 152138 Hom.: 36050 Cov.: 35 AF XY: 0.658 AC XY: 48965 AN XY: 74382

Gnomad4 AFR AF: 0.393

Gnomad4 AMR AF: 0.645

Gnomad4 ASJ AF: 0.800

Gnomad4 EAS AF: 0.620

Gnomad4 SAS AF: 0.600

Gnomad4 FIN AF: 0.760

Gnomad4 NFE AF: 0.816

Gnomad4 OTH AF: 0.695

Alfa AF: 0.763 Hom.: 11462

Bravo AF: 0.647

Asia WGS AF: 0.610 AC: 2124 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.2868+6C>T in intron 20 of PLEC: This variant is not expected to have clinical significance because it has been identified in 45.4% (1842/4060) of African Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs11780911). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 12, 2016	- -

Epidermolysis bullosa simplex with nail dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Epidermolysis bullosa simplex, Ogna type;C2677349:Epidermolysis bullosa simplex 5C, with pyloric atresia;C2931072:Epidermolysis bullosa simplex 5B, with muscular dystrophy;C3150989:Autosomal recessive limb-girdle muscular dystrophy type 2Q;C4225309:Epidermolysis bullosa simplex with nail dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Epidermolysis bullosa simplex 5C, with pyloric atresia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Epidermolysis bullosa simplex 5B, with muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Autosomal recessive limb-girdle muscular dystrophy type 2Q Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Epidermolysis bullosa simplex, Ogna type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.9
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11780911; hg19: chr8-145004546; COSMIC: COSV59644792; COSMIC: COSV59644792;